Systemic lupus erythematosus (SLE) is a devastating illness striking primarily young women in their reproductive years. Treatments for active SLE remain inadequate with significant adverse effects. Response rates for even the most aggressive therapies are capped at 50%. Thus there is a significant need for more effective and safer therapeutic options. Mesenchymal stem cells (MSCs) are stromal cells known to possess significant immunosuppressive properties. Evidence from animal models and uncontrolled trials in patients with SLE supports the effectiveness of allogeneic MSC infusions in reducing SLE disease activity, with remarkably few adverse effects. MSCs are relatively immune-privileged in that they do not express Class II antigens or surface activating markers such as CD80/86, and therefore can be given without cross-matching or any need for bone marrow ablation of the recipient. To date there are no published or in progress controlled trials of MSC therapy compared to standard of care in SLE. We propose a Phase II multicenter placebo controlled trial evaluating efficacy and safety of allogeneic MSCs for the treatment of adults with moderate to severely active SLE. MSCs will be derived from healthy donor umbilical cords and 3 doses of MSCs will be tested. Each of the participating trial sites has a good manufacturing practice (GMP) quality Clean Cell Facility to ensure the quality and safety of the MSCs prior to infusing into study participants. Our primary aim for the proposed trial is to test the hypothesis that patients receiving the MSC infusion will respond better than patients receiving the placebo infusion when added to standard-of-care therapy for active SLE. The primary endpoint will be clinical response at 24 weeks as measured by reduction in disease activity using validated SLE-specific instruments and reduction in corticosteroid dose to d10 mg/day of prednisone or equivalent. Additional endpoints will include MSC dose comparisons, adverse events between groups, steroid-sparing effects, changes in patient-reported quality of life, fatigue, pain and depression, and changes in cellular and serum biomarkers. The R34 Planning Grant will allow us to complete protocol development and set up the administrative and regulatory structures necessary at each of the sites for successful implementation of a multicenter trial of MSCs for patients with active SLE.